The principal objective of the present proposal is to provide pharmacological validation for learned helplessness (LH) in rats as an animal model of human depression and a biological screen for new antidepressant drugs. LH consists of shock escape deficits exhibited by animals previously exposed to inescapable shock. LH will be induced by exposing rats to 80 trials of 5 seconds of inescapable shock at an intensity of 1.O mA (Controls will receive no such shock experience). On the day following initial training, all rats will be tested for acquisition of a simple shuttle response to escape shock. Previously shocked rats show deficits in learning this response. Beginning on day 3, graded intraperitoneal doses of a number of drugs will be tested for their efficacy in reversing this effect. Each animal will be injected daily for 14 days after LH training. In order to examine both acute and chronic drug effects, rats will be tested on days 1, 7 and 14 of injection. In order to insure that rats remain helpless for the 14 day test period, training sessions will also be conducted on days 6 and 13 of injection. Compounds to be used in these studies are: 1) Tricyclic Antidepressants: imipramine, desipramine and amitriptyline; 2) Atypical Antidepressants: mianserin, iprindole, nomifensine and viloxazine; 3) Lithium; 4) Monoamine Oxidase Inhibitor: tranylcypromine; 5) Stimulant: methamphetamine; 6) Neuroleptic: chlorpromazine; 7) Anti-cholinergic: atropine; 8) Sedative-Hypnotic: Chlordiazepoxide; 9) Opiate: morphine; and 10) Antihistamine: cyproheptadine. Data derived from these studies will reveal both the generality of the LH model in detecting a wide variety of clinically effective antidepressant drugs and its specificity for antidepressants. These studies will also determine if chronic antidepressant administration is necessary for reversal of LH, as it is for the alleviation of human depression. In addition, these studies will provide doseresponse data for a number of compounds and will provide preliminary information on the time course of antidepressant effects in this model system. Finally, these data will allow potency comparisions between a large number of antidepressants to determine if their relative potencies in the LH test parallel the relative clinical potencies of these compounds.